Polyamine metabolism has long been a target of cancer chemotherapy. Natural polyamines, such as putrescine, spermidine and spermine, are simple aliphatic amines produced in eukaryotic cells by a highly regulated metabolic apparatus. Spermine is the largest of the three major polyamines involved in polyamine-dependent cell growth, and has a formula of NH.sub.2 (CH.sub.2).sub.3 NH(CH.sub.2).sub.4 NH(CH.sub.2).sub.3 NH.sub.2. The formulas for putrescine and spermidine are NH.sub.2 (CH.sub.2).sub.4 NH.sub.2 and NH.sub.2 (CH.sub.2).sub.4 NH(CH.sub.2).sub.3 NH.sub.2, respectively.
Polyamine levels and the activity of the polyamine biosynthetic apparatus tend to be high in dividing mammalian cells and low in quiescent cells. Previous studies have shown that populations of cells depleted of their polyamine content stop growing and may die.
For example, .alpha.-difluoromethylornithine, often known as "DFMO" or "Eflornithine", is an inhibitor of polyamine biosynthesis. This compound depletes cellular putrescine and spermidine by inhibiting the enzyme ornithine decarboxylase. DFMO is currently in clinical trials as a chemotherapeutic agent for cancer treatment. A somewhat less specific polyamine inhibitor than DFMO, the compound methylglyoxal-bis(guanylhydrazone), known as "MGBG" or "Methyl-GAG", also is being tested as a chemotherapeutic agent. The clinical interest in these drugs reflect the conventional view that polyamine biosynthesis may be a useful target for cancer prevention and treatment. Unfortunately, these compounds have only demonstrated limited success against cancer and other growth related disorders. There are two likely reasons for this limited efficacy.
The first reason involves the extent of depletion of cellular polyamines. Although several compounds are powerful inhibitors of polyamine biosynthesis, they do not completely deplete a cell of its polyamine content. Apparently, cancerous cells are able to scavenge enough natural polyamines needed to live in spite of the use of the inhibitors.
The second reason involves the function of the polyamines. Polyamine biosynthetic inhibitors do not directly attack the functional target of the natural polyamines. Rather, these inhibitors merely reduce the levels of the natural polyamines, which are needed to promote growth.
The limited success of the polyamine inhibitors means that other strategies must be undertaken to reap the full benefit of chemotherapeutic approaches based on the polyamines. The inventive polyamine analogs described herein yield chemotherapeutic benefits not achieved by the polyamine inhibitors.